STAT (signal transducers and activators of transcription), a transcriptional regulator, is a DNA-binding protein whose activity is regulated by stimulations of various cytokines (IL-6, interferon, etc.) or growth factors (EGF, PDGF, etc.). Upon binding of cytokines to their receptors, JAK (Janus protein tyrosine kinase) kinase is activated to phosphorylate tyrosine in STAT (see e.g., Non Patent Documents 1 and 2). Moreover, upon binding of growth factors to their receptors, tyrosine kinase possessed by the growth factor receptors themselves phosphorylates STAT (see e.g., Non Patent Document 3). The phosphorylated STAT is activated by dimerization via its Src homology 2 (SH2) domain. The activated STAT moves into the nucleus where it specifically recognizes and binds particular DNA sequences in the gene promoter regions to induce the transcriptions of many genes. Specifically, STAT is a mediator essential for signal transduction pathways from cell surface to the nucleus and is deeply involved in cell growth or differentiation, etc.
For STAT, 6 different members (STAT1, STAT2, STAT3, STAT4, STAT5, and STAT6) and some isoforms (STAT1α, STAT1β, STAT3α, and STAT3β) are known.
Of them, STAT3, is expressed in the majority of cytomas (see e.g., Non Patent Document 4). Its constitutive activation and overexpression are observed in various cancer cells such as breast cancer, lung cancer, prostatic cancer, head and neck cancer, skin cancer, pancreatic cancer, and ovarian cancer cells, and in cancer cells such as myeloma, brain tumor, melanoma, leukemia lymphoma, and multiple myeloma cells (see e.g., Non Patent Documents 5, 6, and 7). The growth or invasion of these cancer cells is considered to depend on STAT3. Moreover, the abnormal or constitutive expression of STAT3 is also involved in cellular transformation (see e.g., Non Patent Documents 8, 9, and 10). Thus, STAT3 is probably useful as a target molecule for these cancers. Its inhibitor is therefore useful as an anticancer agent.
It has been reported that an antisense oligonucleotide complementary to the translation initiation region of STAT3 actually inhibits TGF-α-stimulated cell growth induced by an epidermal growth factor receptor (EGFR) (see e.g., Non Patent Document 11). It has also been reported that inhibition of STAT3 functions (using antisense, RNAi, peptides, or the like) can suppress the growth of cancer cells and induce apoptosis. This suggests that a STAT3 inhibitor can serve as a therapeutic or preventive drug for cancer.
For example, 6-nitrobenzo[b]thiophene-1,1-dioxide (see e.g., Non Patent Document 12) and a phosphorylated oligopeptide (see e.g., Non Patent Document 13) are known as compounds inhibiting STAT3.
A 1,3,4-oxadiazole-2-carboxamide compound represented by the following formula (A):
(wherein R1 to R4 represent a hydrogen atom, a halogen atom, or the like, R22 represents a hydrogen atom, lower alkyl, aryl, heteroaryl, or the like, and za represents biaryl, or the like)    is known to be useful as a therapeutic drug for cancer (see e.g., Patent Document 1). The following compound represented by the formula (A) wherein R22 is a phenyl group, and za is a biphenyl group is illustrated.
